Polycarbonates and the use thereof for the preparation of bioerosible matrices

ABSTRACT

Polycarbonates of formula (I) wherein a is an integer from 2 to 300; R 1  and R 2  are the same or different and are independently a polyester residue of formula (III) wherein x and y are integers from 1 to 50, R 4  and R 5 , which are the same or different, are aliphatic straight or branched hydrocarbon chains having from 1 to 4 carbon atoms, R 6  is an aliphatic or alicyclic straight or branched chain having from 2 to 18 carbon atoms, or a polyoxyalkylene residue of formula (II), the two groups --R 4  --COO and --R 5  --COO being randomly distributed in the polyester residue, x and y being in any possible ratio from 0 to 100, are synthesized by reacting dihydroxy compounds with 1,1&#39;-carbonyldiimidazole. They are useful for the preparation of bioerosible matrices for biologically active compounds. ##STR1##

This application is a 371 PCT/EP92/01262 filed Jun. 5, 1992.

The present invention relates to polycarbonates of formula (I) ##STR2##wherein a is an integer from 2 to 300;

R¹ and R², which can be the same or different, are an aliphatic oralicyclic straight or branched chain having from 2 to 18 carbon atoms,

or R¹ and R² are a polyoxyalkylene residue of formula (II): ##STR3## inwhich R³ is hydrogen or methyl, n is an integer from 1 to 3 and m is aninteger from 1 to 200,

or a polyester residue of formula (III) ##STR4## wherein x and y areintegers from 1 to 50, R⁴ and R⁵, which can be the same or different,are aliphatic straight or branched hydrocarbon chains having from 1 to 4carbon atoms, R⁶ is an aliphatic or alicyclic straight or branched chainhaving from 2 to 18 carbon atoms, or a polyoxyalkylene residue offormula (II), being intended that the two groups --R⁴ --COO and --R⁵--COO are randomly distributed in the polyester residue, x and y beingin any possible ratio from 0 to 100.

When R¹ and/or R² are alkylene chains, these preferably have from 2 to12 carbon atoms.

When R¹ and/or R² are polyoxyalkylene residues, these are preferablypolyoxyethylene residues of formula (II) wherein R³ is H, n is 1 and mis an integer from 2 to 100.

Polycarbonates in which R¹ and R² are hexylene, decylene, dodecylene,1,4-cyclohexylene, 2,2-dimethyl-1,3-propylene, 2,5-dimethyl-2,5-hexyleneor polyoxyethylene residues are preferred.

Particularly preferred are those polycarbonates in which R¹ and R² areselected from 1,4-cyclohexylene, 2,2-dimethyl-1,3-propylene,2,5-dimethyl-2,5-hexylene or polyoxyethylene residues.

More particularly preferred are those polycarbonates in which R¹ and R²are polyester residues.

Most particularly preferred are those polycarbonates in which R¹ and R²are polyester residues, wherein R⁴ and R⁵ are methylene ormethyl-methylene.

Groups R¹ and R² are preferably different from each other so as to givealternate co-polycarbonates, i.e. having regularly alternated monomericunits.

The invention further relates to a process for the preparation ofcompounds I and the use thereof for the preparation of pharmaceuticalformulations slowly releasing the active principles.

Examples of pharmaceutical formulations in which the drug (activeprinciple) is incorporated in a polymer matrix are well known inliterature: See "Biodegradable Polymers as Drug Delivery Systems", ed.by M. Chasin and R. Langer, Marcel Dekker Inc., New York 1990; "Methodsin Enzymology, Vol. 112, Drug and Enzyme Targeting, Part A", ed. by K.J. Widder and R. Green, Academic Press, Inc., Orlando, Fla. 1985;"Formes Pharmaceutiques Nouvelles", P. Buri, F. Puisieux, E. Doelker andJ. P. Benoit, Technique et Documentation (Lavoisier), Paris 1985;"Biodegradable Polymers for controlled release of peptides andproteins", F. G. Hutchison and B. J. To. Furr, in Drug Carrier Systems,F. H. D. Roerdink and A. M. Kroom eds., John Wiley and Sons, Chichester,1989; and "Controlled Release of Biologically Active Agents" by RichardBaker, John Wiley and Sons, New York 1987.

Aliphatic polycarbonates are known for example from DE 2546534,JP-62241920, JP-1009225, and they were proposed as plastifiers,intermediates for the preparation of polyurethanes or for specialapplications, such as the preparation of substrates for optical disks.The polycarbonates of the invention, having intrinsic viscosities inchloroform at 30° C. ranging from 0.05 dl/g to 2 dl/g, preferably from0.077 to 0.32 dl/g, have biodegradability characteristics which makethem useful for the preparation of bioerosible matrices.

Therefore, the invention also relates to pharmaceutical compositionsproviding a slow release of the active principles from bioerosiblematrices comprising polycarbonates of formula (I).

Polymers of formula I are prepared by reacting diols of formula (IV) or(V)

    HO--R.sup.1 --OH                                           (IV)

    HO--R.sup.2 --OH                                           (V)

wherein R¹ and R² are as defined above, with 2 moles of1,1'-carbonyldiimidazole, to give diimidazolyl formates of formula (VI)or (VII) ##STR5## which are in their turn reacted with diols of formula(IV) or (V).

When R¹ and/or R² are polyester residues, then the compounds (IV) and(V) are synthetized under N₂ stream, at 200° C., starting from a mixturecontaining HO--R⁴ --COOH and HO--R⁵ --COOH in the desired ratio and1-10% w/w of HO--R⁶ --OH and variable amounts of water.

The process is effected in aprotic solvents such as aliphatic oraromatic hydrocarbons, halogenated hydrocarbons, acetonitrile,dimethylsulfoxide, dimethylformamide, at a temperature from roomtemperature to the boiling temperature of the reaction mixture.

The following examples further illustrate the invention.

EXAMPLE 1

4.97 g of 1,1'-carbonyldiimidazole are added to an anhydrous solution of3.05 g of polyethylene glycol 600 in 100 ml of "alcohol-free"chloroform. After 30 minutes the solution is stirred in the presence of75 ml of water for 15 minutes; then it is extracted with 4×25 ml ofwater and dried over sodium sulfate. The organic phase is filtered,solvent is evaporated off to obtain 3.82 g of diimidazolyl formate,2.1249 g of which are mixed with 1.00 ml of a 1,6-hexanediol anhydroussolution in admixture with 1:1 "alcohol-free"chloroform/dimethylsulfoxide having a concentration of 0.327 g/ml. Afteraddition of 0.7538 g of imidazole and of a 1:1chloroform/dimethylsulfoxide mixture to complete dissolution of thereagents, the solution is placed into a 60° C. bath for four days, afterthat it is diluted to 150 ml with chloroform, extracted with 5×30 ml ofwater, dried over anhydrous sodium sulfate and filtered. By evaporationof the solvent, 1.56 g of polycarbonate are obtained, which is liquid at20° C. and has an intrinsic viscosity of 0.25 dl/g, measured inchloroform at 30° C. by means of Ubbelohde viscosimeter.

EXAMPLE 2

The procedure of example 1 is followed, using triethylene glycol insteadof polyethylene glycol 600. The amounts are as follows:

1.21 g of triethylene glycol

6.34 g of 1,1'-carbonyldiimidazole.

2.51 g of diimidazolyl formate are obtained, 2.2111 g of which arereacted with 3.67 ml of a 1,6-hexanediol anhydrous solution ofconcentration 0.215 g/ml and 1.7656 g of imidazole, to obtain 1.90 g ofpolycarbonate, which is liquid at 20° C. and has an intrinsic viscosityof 0.16 dl/g in chloroform at 30° C.

EXAMPLE 3

The procedure of example 1 is followed, replacing polyethylene glycol600 with triethylene glycol and of the 1,6-hexanediol with1,10-decanediol. The amounts are as follows:

0.97 g of triethylene glycol

5.08 g of 1,1'-carbonyldiimidazole.

2.01 g of diimidazolyl formate are obtained, 1.7395 g of which arereacted with 3.37 ml of a 1,10-decanediol solution of concentration0.278 g/ml and 1.3988 g of imidazole. 1.83 g of polycarbonate areobtained, having melting point of 26°-28° C. and viscosity of 0.17 dl/gin chloroform at 30° C.

EXAMPLE 4

The procedure of example 1 is followed, replacing polyethylene glycol600 with triethylene glycol and 1,6-hexanediol with 1,12-dodecanediol.The amounts are as follows:

0.73 g of triethylene glycol

3.80 g of 1,1'-carbonyldiimidazole.

1.51 g of diimidazolyl formate are obtained, 1.2493 g of which arereacted with 2.41 ml of a 1,12-dodecanediol solution of concentration0.312 g/ml and 0.9845 g of imidazole. 1.49 g of polycarbonate areobtained, having melting point of 34°-35° C. and intrinsic viscosity of0.19 dl/g in chloroform at 30° C.

EXAMPLE 5

The procedure of example 1 is followed, using2,2-dimethyl-1,3-propanediol instead of both polyethylene glycol 600 and1,6-hexanediol. The amounts are as follows:

1.55 g of 2,2-dimethyl-1,3-propanediol

8.94 g of 1,1'-carbonyldiimidazole.

4.06 g of diimidazolyl formate are obtained, 3.4482 g of which arereacted with 4.63 ml of a 2,2-dimethyl-1,3-propanediol solution ofconcentration 0.259 g/ml and 2.8874 g of imidazole. 2.30 g ofpolycarbonate are obtained, having melting point of 70°-74° C. andintrinsic viscosity of 0.077 dl/g in chloroform at 30° C.

EXAMPLE 6

The procedure of example 1 is followed, replacing polyethylene glycol600 with 2,2-dimethyl-1,3-propanediol and 1,6-hexanediol with1,10-decanediol. The amounts are as follows:

1.62 g of 2,2-dimethyl-1,3-propanediol

9.37 g of 1,1'-carbonyldiimidazole.

4.25 g of diimidazolyl formate are obtained, 3.5386 g of which arereacted with 8.80 ml of a 1,10-decanediol solution of concentration0.243 g/ml and 3.1437 g of imidazole. 3.86 g of polycarbonate areobtained, which is liquid at 20° C., and has an intrinsic viscosity of0.21 dl/g in chloroform at 30° C.

EXAMPLE 7

The procedure of example 1 is followed, using 1,10-decanediol instead ofboth polyethylene glycol 600 and 1,6-hexanediol. The amounts are asfollows:

1.30 g of 1,10-decanediol

4.64 g of 1,1'-carbonyldiimidazole.

2.43 g of diimidazolyl formate are obtained, 1.8584 g of which arereacted with 3.80 ml of a 1,10-decanediol solution of concentration0.249 g/ml and 1.3768 g of imidazole. 2.06 g of polycarbonate areobtained, having melting point of 55°-57° C. and intrinsic viscosity of0.19 dl/g in chloroform at 30° C.

EXAMPLE 8

The procedure of example 1 is followed, using 1,10-decanediol instead ofpolyethylene glycol 600 and 1,4-cyclohexanediol instead of1,6-hexanediol. The amounts are as follows:

1.18 g of 1,10-decanediol

4.08 g of 1,1'-carbonyldiimidazole.

2.24 g of diimidazolyl formate are obtained, 1.7343 g of which arereacted with 2.45 ml of a 1,4-cyclohexanediol solution of concentration0.229 g/ml and 1.4509 g of imidazole. 1.44 g of polycarbonate areobtained, having melting point of 91°-100° C. and intrinsic viscosity of0.15 del/g in chloroform at 30° C.

EXAMPLE 9

8.39 g of 1,1'-carbonyldiimidazole are dissolved in an anhydroussolution prepared from 1.42 g of 1,4-cyclohexanediol, 20 ml ofdimethylsulfoxide and 100 ml of "alcohol-free" chloroform. The procedureof example 1 is followed, to obtain 3.50 g of diimidazolyl formate,2.7414 g of which are reacted with 6.82 ml of a 1,10 decanediol solutionof concentration 0.243 g/ml and 6.8294 g of imidazole. 3.12 g ofpolycarbonate are obtained having melting point of 88°-93° C. andintrinsic viscosity of 0.13 dl/g in chloroform at 30° C.

EXAMPLE 10

The procedure of example 1 is followed, replacing 1,6-hexanediol with1,10-decanediol. The amounts are as follows:

2.45 g of polyethylene glycol 600

2.48 g of 1,1'-carbonyldiimidazole.

2.78 g of diimidazolyl formate are obtained, 2.3646 g of which arereacted with 2.46 ml of a 1,10-decanediol solution of concentration0.217 g/ml and 0.8538 g of imidazole. 2.19 g of polycarbonate areobtained, which is liquid at 20° C., having intrinsic viscosity of 0.28dl/g in chloroform at 30° C.

EXAMPLE 11

The procedure of example 1 is followed, replacing 1,6-hexanediol with2,2-dimethyl-1,3-propanediol. The amounts are as follows:

2.18 g of polyethylene glycol 600

2.23 g of 1,1'-carbonyldiimidazole.

2.47 g of diimidazolyl formate are obtained, 1.9386 g of which arereacted with 1.03 ml of a 2,2-dimethyl-1,3-propanediol solution ofconcentration 0.255 g/ml and 0.6935 g of imidazole. 1.74 g ofpolycarbonate are obtained, which is liquid at 20° C., having intrinsicviscosity of 0.21 dl/g in chloroform at 30° C.

EXAMPLE 12

The procedure of example 1 is followed, replacing 1,6-hexanediol with1,4-cyclohexanediol. The amounts are as follows:

2.83 g of polyethylene glycol 600

3.16 g of 1,1'-carbonyldiimidazole.

3.24 g of diimidazolyl formate are obtained, 2.6828 g of which arereacted with 1.92 ml of a 1,4-cyclohexanediol solution of concentration0.210 g/ml and 1.0459 g of imidazole. 2.39 g of polycarbonate areobtained, which is liquid at 20° C., having intrinsic viscosity of 0.26dl/g in chloroform at 30° C.

EXAMPLE 13

The procedure of example 1 is followed, replacing polyethylene glycol600 with 2,2-dimethyl-1,3-propanediol. The amounts are as follows:

0.78 g of 2,2-dimethyl-1,3-propanediol

4.54 g of 1,1'-carbonyldiimidazole.

2.07 g of diimidazolyl formate are obtained, 1.4731 g of which arereacted with 2.67 ml of a 1,6-hexanediol solution of concentration 0.223g/ml and 1.4725 g of imidazole. 1.32 g of polycarbonate are obtained,which is liquid at 20° C., having intrinsic viscosity of 0.17 dl/g inchloroform at 30° C.

EXAMPLE 14

The procedure of example 1 is followed, replacing polyethylene glycol600 with 2,2-dimethyl-1,3-propanediol and 1,6-hexanediol with1,12-dodecanediol. The amounts are as follows:

0.95 g of 2,2-dimethyl-1,3-propanediol

5.40 g of 1,1'-carbonyldiimidazole.

2.58 g of diimidazolyl formate are obtained, 1.8902 g of which arereacted with 5.66 ml of a 1,12-dodecanediol solution of concentration0.231 g/ml and 1.5611 g of imidazole. 1.92 g of polycarbonate areobtained, which is liquid at 20° C., having intrinsic viscosity of 0.19dl/g in chloroform at 30° C.

EXAMPLE 15

The procedure of example 1 is followed, using 1,6-hexanediol instead ofpolyethylene glycol 600. The amounts are as follows:

0.87 g of 1,6-hexanediol

4.99 g of 1,1'-carbonyldiimidazole.

2.08 g of diimidazolyl formate are obtained, 1.4806 g of which arereacted with 2.80 ml of a 1,6-hexanediol solution of concentration 0.204g/ml and 1.5163 g of imidazole. 1.31 g of polycarbonate are obtained,having melting point of 58°-60° C. and intrinsic viscosity of 0.18 dl/gin chloroform at 30° C.

EXAMPLE 16

The procedure of example 1 is followed, using 1,6-hexanediol instead ofpolyethylene glycol 600 and 1,10-decanediol instead of 1,6-hexanediol.The amounts are as follows:

1.04 g of 1,6-hexanediol

5.31 g of 1,1'-carbonyldiimidazole.

2.43 g of diimidazolyl formate are obtained, 1.7387 g of which arereacted with 4.10 ml of a 1,10-decanediol solution of concentration0.241 g/ml and 1.7457 g of imidazole. 1.72 g of polycarbonate areobtained, having melting point of 40°-44° C. and intrinsic viscosity of0.17 dl/g in chloroform at 30° C.

EXAMPLE 17

The procedure of example 1 is followed, using 1,10-decanediol instead ofpolyethylene glycol 600 and 1,12-dodecanediol instead of 1,6-hexanediol.The amounts are as follows:

1.04 g of 1,10-decanediol

3.56 g of 1,1'-carbonyldiimidazole.

2.05 g of diimidazolyl formate are obtained, 1.3943 g of which arereacted with 3.59 ml of a 1,12-dodecanediol solution of concentration0.217 g/ml and 1.0176 g of imidazole. 1.41 g of polycarbonate areobtained, having melting point of 50°-52° C. and intrinsic viscosity of0.21 dl/g in chloroform at 30° C.

EXAMPLE 18

The procedure of example 1 is followed, using polyethylene glycol 1000instead of polyethylene glycol 600. The amounts are as follows:

4.10 g of polyethylene glycol 1000

2.96 g of 1,1'-carbonyldiimidazole.

3.84 g of diimidazolyl formate are obtained, 2.8818 g of which arereacted with 1.25 ml of a 1,6-hexanediol solution of concentration 0.248g/ml and 0.6723 g of imidazole. 2.46 g of polycarbonate are obtained,which is liquid at 20° C., having viscosity of 0.32 dl/g in chloroformat 30° C.

EXAMPLE 19

The procedure of example 1 is followed, using 1,6-hexanediol instead ofpolyethylene glycol 600 and 1,4-cyclohexanediol instead of1,6-hexanediol. The amounts are as follows:

1.04 g of 1,6-hexanediol

5.19 g of 1,1'-carbonyldiimidazole.

2.53 g of diimidazolyl formate are obtained, 1.6105 g of which arereacted with 2.83 ml of a 1,4-cyclohexanediol solution of concentration0.216 g/ml and 1.7318 g of imidazole. 1.45 g of polycarbonate areobtained, having melting point of 110°-115° C. and intrinsic viscosityof 0.16 dl/g in chloroform at 30° C.

EXAMPLE 20

The procedure of example 1 is followed, using2,2-dimethyl-1,3-propanediol instead of polyethylene glycol 600 and1,4-cyclohexanediol instead of 1,6-hexanediol. The amounts are asfollows:

0.80 g of 2,2-dimethyl-1,3-propanediol

5.06 g of 1,1'-carbonyldiimidazole.

2.01 g of diimidazolyl formate are obtained, 1.4315 g of which arereacted with 2.74 ml of a 1,4-cyclohexanediol solution of concentration0.208 g/ml and 1.4337 g of imidazole. 1.23 g of polycarbonate areobtained, having melting point of 142°-148° C. and intrinsic viscosityof 0.10 dl/g in chloroform at 30° C.

EXAMPLE 21

The procedure of example 1 is followed, replacing polyethylene glycol600 with triethylene glycol and 1,6-hexanediol with 1,4-cyclohexanediol.The amounts are as follows:

1.31 g of triethylene glycol

5.97 of 1,1'-carbonyldiimidazole.

2.72 g of diimidazolyl formate are obtained, 1.9292 g of which arereacted with 3.25 ml of a 1,4-cyclohexanediol solution of concentration0.204 g/ml and 1.3529 g of imidazole. 1.65 g of polycarbonate areobtained, having melting point of 31°-34° C. and intrinsic viscosity of0.14 dl/g in chloroform at 30° C.

EXAMPLE 22

The procedure of example 1 is followed, replacing polyethylene glycol600 with 2,5-dimethyl-2,5-hexanediol and 1,6-hexanediol with1,10-decanediol. The amounts are as follows:

1.19 g of 2,5-dimethyl-2,5-hexanediol

4.33 g of 1,1'-carbonyldiimidazole.

2.54 g of diimidazolyl formate are obtained, 1.9980 g of which arereacted with 4.49 ml of a 1,10-decanediol solution of concentration0.232 g/ml and 1.6272 g of imidazole. 1.98 g of polycarbonate areobtained, which is liquid at 20° C., having viscosity of 0.23 dl/g inchloroform at 30° C.

EXAMPLE 23

The procedure of example 1 is followed, replacing polyethylene glycol600 with 2,5-dimethyl-2,5-hexanediol and 1,6-hexanediol with triethyleneglycol. The amounts are as follows:

1.12 g of 2,5-dimethyl-2,5-hexanediol

4.87 g of 1,1'-carbonyldiimidazole.

2.38 g of diimidazolyl formate are obtained, 1.7605 g of which arereacted with 3.63 ml of a triethylene glycol solution of concentration0.218 g/ml and 1.3938 g of imidazole. 1.67 g of polycarbonate areobtained, which is liquid at 20° C., having viscosity of 0.16 dl/g inchloroform at 30° C.

EXAMPLE 24

40.00 g of a 90% DL-lactic acid aqueous solution are reacted with 11.26g of glycolic acid and 2.58 g of 1,10-decanediol at a temperature of200° C., with stirring, under nitrogen stream, for 24 hours. After that,the product is thoroughly dried and molecular weight is determined byosmometry (MW: 850). 2.52 g of the resulting oligomer are reacted with1.11 g of 1,10-decanediol diimidazolyl formate (prepared as described inexample 7) and 0.21 g of anhydrous imidazole in 5 ml of "alcohol-free"chloroform at a temperature of 60° C. for 10 days. Then the mixture isdiluted in 70 ml of chloroform, washed with 5×20 ml of water, dried overanhydrous sodium sulfate and filtered. Solvent is evaporated off, toobtain 2.08 g of polycarbonate, which is solid at 25° C., havingintrinsic viscosity of 0.32 dl/g, measured with a Ubbelhode viscosimeterin chloroform at 30° C.

EXAMPLE 25

The procedure of example 24 is followed, using in the first step, forthe preparation of the oligomer, DL-lactic acid, glycolic acid andethylene glycol, instead of 1,10-decanediol. The amounts are as follows:

32.08 g of 90% DL-lactic acid aqueous solution

2.31 g of glycolic acid

3.35 g of ethylene glycol.

30.01 g of the oligomer are obtained, which is thoroughly dried. Themolecular weight is determined by the osometric method (MW: 700). Thesubsequent polymerization steps is also carried out as described inexample 24, using the new oligomer of MW 700 instead of the one of MW850, and 1,10-decanediol diimidazolyl formate. The amounts are asfollows:

2.32 g of oligomer

0.98 g of 1,10-decanediol diimidazolyl formate

0.22 g of anhydrous imidazole.

2.51 g of polycarbonate are obtained, having intrinsic viscosity of 0.30dl/g in chloroform at 30° C.

EXAMPLE 26

The procedure of example 24 is followed, using DL-lactic and glycolicacid in the following amounts:

18.51 g of 90% DL-lactic acid aqueous solution

14.41 g of glycolic acid

2 g of 1,10-decanediol.

31.81 g of oligomer are obtained, of MW: 650, determined by osmometry.4.51 g of said oligomer are reacted with 1.99 g of 1,10-decanedioldiimidazolyl formate (prepared as described in example 7) and 0.38 g ofanhydrous imidazole; the polymer is recovered as in example 24. 4.38 gof polycarbonate are obtained, having intrinsic viscosity of 0.42 dl/gin chloroform at 30° C.

EXAMPLE 27

3.01 g of the oligomer prepared in example 24 (mw: 850) are reacted with1.11 g of 1,1'-carbonyldiimidazole in 6 ml of "alcohol-free" chloroformat a temperature of 60° C.; subsequently, 0.62 g of anhydrous1,10-decanediol and 0.24 g of anhydrous imidazole are added to thereaction mixture, which is left to polymerize for 10 days at 60° C.Finally the product is purified, as described in example 24, to obtain2.88 of polycarbonate, having intrinsic viscosity of 0.32 dl/g inchloroform at 30° C.

EXAMPLE 28

The procedure of example 27 is followed, using the oligomer prepared inexample 24 (MW: 850). The amounts are as follows:

3.66 g of oligomer (MW: 850)

1.35 g of 1,1'-carbonyldiimidazole

5 ml of "alcohol-free" chloroform

0.75 g of 1,10-decanediol diimidazolyl formate

2.05 g of polycarbonate are obtained, having intrinsic viscosity of 0.45dl/g in chloroform at 30° C.

EXAMPLE 29

3.00 g of the oligomer prepared in example 24 (mw: 850) are reacted with1.08 g of 1,4-cyclohexanediol diimidazolyl formate (prepared in example9) and 0.31 g of anhydrous imidazole at 60° C. for 10 days. Theprocedure of example 24 is followed, to obtain 9.00 g of polycarbonate,having intrinsic viscosity of 0.30 dl/g in chloroform at 30° C.

EXAMPLE 30

2.25 g of the oligomer prepared in example 25 (MW: 700) are reacted with1.02 g of 1,1'-carbonyldiimidazole in 5 ml of "alcohol-free" chloroformfor 30 min. Then 2.25 g of the same oligomer MW 700 and 0.22 g ofanhydrous imidazole are added to the reaction mixture, which is left toreact for 10 days at 60° C. Finally the product is purified, asdescribed in example 24, to obtain 4.80 g of polycarbonate, havingintrinsic viscosity of 0.34 dl/g in chloroform at 30° C.

EXAMPLE 31

3.00 g of the oligomer prepared in example 25 (MW: 700) are reacted with1.45 g of triethylene glycol diimidazolyl formate in 5 ml of"alcohol-free" chloroform and 0.30 g of anhydrous imidazole.Diimidazolyl formate is prepared as described in example 2, with thefollowing amounts:

1.30 g of triethylene glycol

6.45 g of 1,1'-carbonyldiimidazole.

The reaction mixture, which is left to react for 10 days at 60° C.Finally the polymer is recovered as described in example 24, to obtain2.98 g of polymer, having intrinsic viscosity of 0.35 dl/g in chloroformat 30° C.

EXAMPLE 32

A mixture consisting of 45 mg of 1,12-dodecanediol-polycarbonate (seeExample 17) and 5 mg of deslorelin (Des-Gly¹⁰, D-Trp⁶, Proethylamide⁹),a LHRH agonist peptide, was melted at 70° C. to obtain a homogeneousmass, which, after cooling at 20° C., was milled and extruded from apiston equipped PTFE tube, under a 100 kg/cm² pressure and at 40° C. Theso obtained cylindric formulation (2 mm diameter, 10 mm length) wassterilized with gamma rays and subsequently used for therapeuticsubcutaneous grafts.

We claim:
 1. A polycarbonate of formula (I) ##STR6## wherein a is aninteger from 2 to 300; R¹ and R² are the same or different, and areindependently a polyester residue of formula (III) ##STR7## wherein xand y are integers from 0 to 50, R⁴ and R⁵, which are the same ordifferent and are aliphatic straight or branched hydrocarbon chainshaving from 1 to 4 carbon atoms, R⁶ is an aliphatic or alicyclicstraight or branched chain having from 2 to 18 carbon atoms, or apolyoxyalkylene residue of formula (II) ##STR8## in which R³ is hydrogenor methyl, n is an integer from 1 to 3 and m is an integer from 1 to200, and said two groups --R⁴ --COO and --R⁵ --COO are randomlydistributed in the polyester residue, x and y being in any ratio from 0to
 100. 2. The polycarbonate according to claim 1 wherein R¹ and R² aredifferent from each other, thus forming alternate co-polycarbonates. 3.The polycarbonate according to claim 1 wherein R⁴ and R⁵ are methyleneor methyl-methylene.
 4. The polycarbonate according to claim 1 whereinsaid R⁴ --COO-- and R⁵ --COO-- are radicals obtained from lactic acidand glycolic acid.
 5. The method of preparation of a polycarbonate offormula (I) ##STR9## wherein a is an integer from 2 to 300; R¹ and R²are the same or different, and are independently a polyester residue offormula (III) ##STR10## wherein x and y are integers from 0 to 50, R⁴and R⁵, which are the same or different and are aliphatic straight orbranched hydrocarbon chains having from 1 to 4 carbon atoms, R⁶ is analiphatic or alicyclic straight or branched chain having from 2 to 18carbon atoms, or a polyoxyalkylene residue of formula (II) ##STR11## towhich R³ is hydrogen or methyl, n is an integer from 1 to 3 and m is aninteger from 1 to 200, and said two groups --R⁴ --COO and --R⁵ --COO arerandomly distributed in the polyester residue, x and y being in anyratio from 0 to 100, which consists of the steps of1) reacting 2 molesof 1,1¹ -carbonyldiimidazole with a diol of formula (IV) or (V)

    HO--R.sup.1 --OH                                           (IV)

    HO--R.sup.2 --OH                                           (V)

wherein R¹ and R² are as defined hereinabove, in an organic aproticsolvent which is a member selected from the group consisting ofchloroform, acetonitrile, dimethylsulfoxide, and dimethylformamide, at atemperature from room temperature to the boiling temperature of thereaction mixture, whereby a diimidazole formate of formula VI or VII isobtained, ##STR12## wherein R¹ and R² are the same as hereinabove; and2) then reacting said compound of formula VI or VII with a diol offormula (IV) or (V)

    HO--R.sup.1 --OH                                           (IV)

    or

    HO--R.sup.2 --OH                                           (V)

wherein R¹ and R² are the same as hereinabove, with imidazole in anorganic aprotic solvent followed by extraction with water, drying saidsolvent and recovering said polycarbonate of formula (I) by evaporationof said organic aprotic solvent.
 6. The method according to claim 5wherein said diol in step 1) is a member selected from the groupconsisting of polyethylene glycol 600, triethylene glycol,2,2-dimethyl-1,3-propanediol, 1,10-decanediol, 1,4-cyclohexanediol,polyethylene glycol 1000 and 2,5-dimethyl 2,5-hexanediol.
 7. The methodaccording to claim 5 wherein said diol in step 2) is a member selectedfrom the group consisting of 1,6-hexanediol, 1,10-decanediol,1,12-dodecanediol, 2,2-dimethyl-1,3-propanediol, 1,4-cyclohexanediol andtriethylene glycol.
 8. A pharmaceutical composition containing an activecomponent and a bioerosible matrix comprising the polycarbonate offormula (I) according to claim 5.